Hematopoietic Cell Transplantation In Complete Remission Research Articles

Allogeneic Hematopoietic Cell Transplantation for Acute Megakaryocytic Leukemia: A Single Center Study

Introduction Acute megakaryocytic leukemia (AMKL) comprises 4-15% of all acute myeloid leukemia (AML) diagnoses in pediatric patients. Unlike patients with Down syndrome who have a >80% expected survival with dose-reduced chemotherapy, the 5-year overall survival (OS) in patients with de novo AMKL is dismal and ranges between 14-49%. While treatment intensification has marginally improved the outcome of these patients over the last few decades, the role of hematopoietic cell transplantation (HCT) in these patients in first complete remission (CR) is often debated. To better define the role of HCT, we evaluated the outcomes of pediatric patients who underwent their first HCT for AMKL at our institution from October 1990 to January 2021. Methods We conducted a retrospective analysis using patient, disease, and transplant-related data collected during routine clinical care and evaluated these variables for their prognostic value. Kaplan-Meier curves were generated to estimate survival probabilities in pre-specified groups and compared using the log-rank test. Multivariable analysis was performed using Cox proportional hazards models to assess the role of various patient and transplant-related factors on survival. The cumulative incidence of relapse (with death as competing risk) was estimated by the Fine-Gray multivariable models and compared using Gray's test. Results Our study included 53 patients. The median age at HCT was 2.3 (range 0.9-19.7) years. The median time of follow-up was 10.3 (range 0.9-346.6) months. At the time of HCT, 56.6% of patients were in CR1, 5.7% were in CR2 and 37.7% had active/refractory disease. Nine (17%) patients received an HCT from a matched sibling donor, 25 (47.2%) from a matched unrelated donor, and 19 (35.8%) from a haploidentical donor. Twenty-two (41.5%) patients relapsed after HCT at a median duration of 2.8 (range 0.6-10.5) months, and 31 (58.5%) patients died at a median duration of 4.3 (range 0.9-15.9) months. The one-year OS estimates trended higher in patients undergoing transplant in more recent decades (1990-2000: 32%, 2000-2010: 46%, 2010-2020: 67%; P = 0.2). Patients who underwent HCT in CR had a significantly higher 1-year OS (57% versus 30%; P < 0.001) and decreased rate of relapse (24% versus 70%; P < 0.001) compared to those who underwent HCT with active/refractory disease. Similarly, in multivariable analysis, being in CR during HCT was associated with improved OS (Hazard Ratio [HR] 0.17, 95% Confidence Interval [CI] 0.07-0.41) and decreased risk of relapse (HR 0.18, 95% CI 0.07-0.46) after adjusting for other pre-specified variables. Conclusion While the overall outcome of patients who undergo HCT for AMKL has improved in the last few decades, it remains suboptimal. Patients who underwent HCT in CR had superior outcomes. Our data supports the notion that patients with de novo AMKL would benefit from HCT when they first achieve CR while we await novel strategies in treating relapsed or refractory AMKL.

Allogeneic Hematopoietic Cell Transplantation for Patients with Relapsed Acute Promyelocytic Leukemia

Although autologous hematopoietic cell transplantation (HCT) is an established therapy for patients with relapsed acute promyelocytic leukemia (APL) after returning to complete remission (CR), the role of allogeneic HCT remains unclear for treating relapsed APL. This study aimed to investigate allogeneic HCT outcomes in patients with relapsed APL, focusing particularly on those who underwent transplantation in non-CR and those who had relapsed after prior autologous HCT. We retrospectively analyzed Japanese nationwide transplantation registry data of patients with relapsed APL age ≥16 years who underwent allogeneic HCT between 2006 and 2020. A total of 195 patients were eligible for this analysis, including 69 who underwent transplantation in non-CR and 55 who relapsed after prior autologous HCT. The median duration of follow-up for survivors was 5.4 years. Multivariate analysis revealed that both non-CR at transplantation (hazard ratio [HR], 1.74; 95% confidence interval [CI], 1.12 to 2.71; P=.014) and prior autologous HCT (HR, 2.10; 95% CI, 1.28 to 3.44; P=.013) were associated with higher risks of overall mortality. The 5-year overall survival (OS) rates for patients who underwent transplantation in CR and non-CR were 58% and 39%, respectively (P=.085), if they did not have a history of prior autologous HCT. In the patients who had relapsed after prior autologous HCT, the 5-year OS rate was 47% for those who underwent allogeneic HCT in CR and 6% for those who did so in non-CR (P=.001). Allogeneic HCT still provides an opportunity for long-term survival for certain patients with relapsed APL for whom autologous HCT is unlikely to be effective. The dismal outcome of those with prior autologous HCT who underwent allogeneic HCT in non-CR poses a significant therapeutic challenge.

Long-term results of reduced-intensity conditioning allogeneic hematopoietic cell transplantation for older patients with acute myeloid leukemia: a retrospective analysis of 10-year follow-up data.

The long-term outcomes of allogeneic hematopoietic cell transplantation (HCT) with reduced-intensity conditioning (RIC) remain inconclusive. To address this issue, we conducted a nationwide registry-based study of patients with acute myeloid leukemia (AML) age 50 years or older who underwent allogeneic HCT in complete remission using RIC (n = 284) or myeloablative conditioning (MAC, n = 190) between 2002 and 2007. The median follow-up period for surviving patients was 10.1 years for RIC recipients and 10.4 years for MAC recipients. The 10-year probabilities of overall survival, relapse, and non-relapse mortality were 36.4%, 30.0%, and 35.7% for RIC recipients, and 39.8%, 26.3%, and 35.5% for MAC recipients, respectively. Multivariate analysis revealed that the conditioning intensity did not affect overall mortality (P = 0.184), relapse (P = 0.904), or non-relapse mortality (P = 0.387). For the 218 patients qualifying for propensity score-matched pairing (109 pairs), RIC was found to be associated with similar survival (P = 0.095) and relapse (P = 0.467), and significantly lower non-relapse mortality (P = 0.046) compared with MAC. Our results confirm the long-term efficacy of RIC allogeneic HCT for older patients with AML and mitigate concerns over an increase in late relapse.

Measurable residual disease at myeloablative allogeneic transplantation in adults with acute lymphoblastic leukemia: a retrospective registry study on 2780 patients from the acute leukemia working party of the EBMT

BackgroundAssessment of measurable residual disease (MRD) is rapidly transforming the therapeutic and prognostic landscape of a wide range of hematological malignancies. Its prognostic value in acute lymphoblastic leukemia (ALL) has been established and MRD measured at the end of induction is increasingly used to guide further therapy. Although MRD detectable immediately before allogeneic hematopoietic cell transplantation (HCT) is known to be associated with poor outcomes, it is unclear if or to what extent this differs with different types of conditioning.MethodsIn this retrospective registry study, we explored whether measurable residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia is associated with different outcomes in recipients of myeloablative total body irradiation (TBI)-based versus chemotherapy-based conditioning. We analyzed outcomes of 2780 patients (median age 38 years, range 18–72) who underwent first HCT in complete remission between 2000 and 2017 using sibling or unrelated donors.ResultsIn 1816 of patients, no disease was detectable, and in 964 patients, MRD was positive. Conditioning was TBI-based in 2122 (76%) transplants. In the whole cohort MRD positivity was a significant independent factor for lower overall survival (OS) and leukemia-free survival (LFS), and for higher relapse incidence (RI), with respective hazard ratios (HR, 95% confidence intervals) of 1.19 (1.02–1.39), 1.26 (1.1–1.44), and 1.51 (1.26–1.8). TBI was associated with a higher OS, LFS, and lower RI with HR of 0.75 (0.62–0.90), 0.70 (0.60–0.82), and 0.60 (0.49–0.74), respectively. No significant interaction was found between MRD status and conditioning. When investigating the impact of MRD separately in the TBI and chemotherapy-based conditioning cohorts by multivariate analysis, we found MRD positivity to be associated with lower OS and LFS and higher RI in the TBI group, and with higher RI in the chemotherapy group. TBI-based conditioning was associated with improved outcomes in both MRD-negative and MRD-positive patients.ConclusionsIn this large study, we confirmed that patients who are MRD-negative prior to HCT achieve superior outcomes. This is particularly apparent if TBI conditioning is used. All patients with ALL irrespective of MRD status benefit from TBI-based conditioning in the myeloablative setting.

The Role of Measurable Residual Disease (MRD) at Time of Allogeneic Hematopoietic Cell Transplantation in Adults with Acute Lymphoblastic Leukemia Transplanted after Myeloablative Conditioning. A Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Assessment of measurable residual disease (MRD) is rapidly transforming the therapeutic and prognostic landscape of a wide range of hematological malignancies. Its prognostic value in acute lymphoblastic leukemia (ALL) has been established and MRD measured at the end of induction is increasingly used to guide further therapy. Although MRD detectable immediately before allogeneic hematopoietic cell transplantation (HCT) is known to be associated with poor outcomes, it is unclear if or to what extent this differs with different types of conditioning. Therefore, in this retrospective multicenter study we explored if MRD detectable before allogeneic HCT for ALL is associated with different outcomes in recipients of myeloablative TBI-based versus chemotherapy-based conditioning. We analyzed outcomes of 2780 patients (median age 38 years, range 18-72) who underwent first HCT in complete remission between 2000 and 2017 using sibling or unrelated 9/10 or 10/10 matched donors. In 1816 of these patients no disease was detectable before transplantation and in 964 patients MRD was detectable (MRD positivity). Conditioning was TBI-based in 2122 (76%) transplants. In the whole cohort MRD positivity was a significant independent factor for lower overall survival (OS) and leukemia-free survival (LFS), and for higher relapse incidence (RI), with respective hazard ratios (HR, 95% confidence intervals) of 1.19 (1.02-1.39), 1.26 (1.1-1.44), 1.51 (1.26-1.8). TBI was associated with a better OS, LFS and RI with HR of 0.75 (0.62-0.90), 0.70 (0.60-0.82) and 0.60 (0.49-0.74), respectively. No significant interaction was found between MRD status and conditioning. When investigating the impact of MRD separately in the TBI and chemotherapy-based conditioning cohorts by multivariate analysis, we found MRD positivity to be associated with lower OS (HR 1.26, 1.05-1.51) and LFS (HR 1.3,1.1-1.53), and higher RI (HR 1.53, 1.23-1.9) in the TBI group, and with higher RI (HR 1.58, 1.13-2.21) in the chemotherapy group. There was no significant association between MRD and other outcomes in this last cohort. TBI based conditioning was associated with improved OS, LFS, and RI in both MRD negative and MRD positive patients (figure). In this large study we confirmed that patients who are MRD negative prior to HCT achieve superior outcomes. This is particularly apparent if TBI conditioning is used. All patients with ALL irrespective of MRD status benefit from TBI based conditioning in myeloablative setting.

Incidence of Acute Graft-Versus-Host Disease and Survival after Allogeneic Hematopoietic Cell Transplantation over Time: A Study from the Transplant Complications and Chronic Malignancies Working Party of the EBMT

INTRODUCTIONAcute graft-versus-host disease (aGvHD) remains a serious complication of allogeneic hematopoietic cell transplantation (HCT) and negatively impacts on patients' outcome. Over recent years improvements in GvHD prophylaxis, HLA typing, donor selection, treatment and supportive care have been achieved. However, it is unknown whether these changes have resulted in improved outcome of patients undergoing allogeneic HCT and particularly in those patients diagnosed with aGvHD and in need of systemic immunosuppressive therapy. METHODSWe examined outcome following diagnosis of grades II-IV and grades III-IV aGvHD according to time period and investigated effects according to maximum overall grade of aGvHD. Between 1990 and 2015, 126 838 patients with a median age of 46.4 (range, 18-83.8) years with malignant disease received a first allogeneic sibling (53.9%) or unrelated donor (46.1%) blood (74.5%) or marrow (25.5%) transplant after myeloablative (58.9%) or reduced-intensity (41.1%) conditioning. Sixty-two percent of patients were in complete remission (CR) at HCT. RESULTSIncidences of aGvHD grades II-IV by 100 days significantly (p<0.001) decreased from 40% for 1990-1995, to 37% for 1996-2000, 31% for 2001-2005, 29% for 2006-2010 and 28% for 2010-2015. In univariate analysis for the whole study population, incidence of aGvHD grades II-IV was higher in patients with an unrelated donor (33% vs 29%, p<0.001), a female donor compared to a male donor for a male recipient (33% vs 31%, p<0.001), and patients not in CR at HCT (33% vs 29%, p<0.001) whereas reduced-intensity conditioning (RIC) (27% vs 33%, p<0.001), and in vivo T-cell depletion (TCD) (27% vs 33%, p<0.001) were associated with a lower incidence. Incidences of aGvHD grades III-IV by 100 days significantly (p<0.001) decreased from 17% for 1990-1995, to 15% for 1996-2000, 13% for 2001-2005, 11% for 2006-2010 and 11% for 2010-2015.The median (range) follow-up was 217.6 (213.4-221.7) months, 169.9 (167.6-172.9) months, 129 (127.3-130.8) months, 81.3 (80.5-82.1) months and 29.7 (29.2-30.2) months for 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2010-2015. For the total study population, 3-year overall survival (OS) significantly (p<0.001) increased from 49% for 1990-1995, to 50% for 1996-2000, 51% for 2001-2005, 53% for 2006-2010 and 54% for 2010-2015, respectively. 3-year nonrelapse mortality (NRM) significantly (p<0.001) decreased from 33% for 1990-1995, to 29% for 1996-2000, 24% for 2001-2005, 23% for 2006-2010 and 23% for 2010-2015. In univariate analysis, OS was better after related donor HCT (55% vs. 49%, p<0.001), and HCT in CR (58% vs 41%, p<0.001) whereas female donor compared to male donor for a male recipient (50% vs 52%, p<0.001), use of antithymocyte globulin (ATG) (51% vs 53%, p<0.001), and in vivo TCD (51% vs 55%, p<0.001) were associated with worse OS.The OS of patients experiencing aGvHD grades II-IV was 66% at 6 months and decreased to 43% at 36 months after HCT. Survival at 36 months after aGvHD grades II-IV increased significantly (p<0.001) from 39% to 40%, 43%, 44% and 45% after HCT in the periods 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2010-2015. In univariate analysis, aGvHD grades II-IV-associated 3-year OS was significantly improved after myeloablative conditioning (45% vs 41%, p<0.001), related donor HCT (45% vs. 41%, p<0.001), and HCT in CR compared to no CR (49% vs 33%, p<0.001) whereas female donor for a male recipient (40% vs 43%, p<0.001), use of ATG (42% vs 44%, p<0.001), and in vivo TCD (41% vs 45%, p<0.001) were associated with worse aGvHD-associated OS. aGvHD grades III-IV-associated OS was 46% at 6 months and decreased to 27% 36 months after HCT. Survival at 36 months after aGvHD grades III-IV increased significantly (p<0.001) from 49% to 50%, 51%, 53% and 54% after HCT in the periods 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2010-2015. In univariate analysis, aGvHD grades III-IV-associated 3-year OS was improved after related donor HCT (29% vs. 25%, p<0.001), and HCT in CR compared to no CR (31% vs 26%, p<0.001) whereas use of ATG (25% vs 28%, p<0.001), and in vivo TCD (25% vs 29%, p<0.001) were associated with worse aGvHD grades III-IV-associated OS. CONCLUSIONSIncidences of aGvHD grades II-IV and grades III-IV decreased over time and aGvHD-associated survival increased over recent years resulting in improved survival of patients undergoing allogeneic HCT for malignant disease. DisclosuresGreinix:Gilead: Speakers Bureau; Roche: Speakers Bureau; Therakos: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs. Mohty:MaaT Pharma: Consultancy, Honoraria.

Allogeneic Hematopoietic Cell Transplantation for Adult T Cell Acute Lymphoblastic Leukemia

Allogeneic hematopoietic cell transplantation (HCT) is recommended for patients with T cell acute lymphoblastic leukemia (T-ALL) in second or later complete remission (CR) and high-risk patients in first CR. Given its relative rarity, data on outcomes of HCT for T-ALL are limited. We conducted a multicenter retrospective cohort study using data from 208 adult patients who underwent HCT between 2000 and 2014 to describe outcomes of allogeneic HCT for T-ALL in the contemporary era. The median age at HCT was 37 years, and the majority of patients underwent HCT in CR, using total body irradiation (TBI)-based myeloablative conditioning regimens. One-quarter of the patients underwent alternative donor HCT using a mismatched, umbilical cord blood, or haploidentical donor. With a median follow up of 38 months, overall survival at 5 years was 34%. The corresponding cumulative incidence of non-relapse mortality and relapse was 26% and 41%, respectively. In multivariable analysis, factors significantly associated with overall survival were the use of TBI (HR, 0.57; P = .021), age >35 years (HR, 1.55; P = .025), and disease status at HCT (HR, 1.98; P = .005 for relapsed/refractory disease compared with CR). Relapse was the most common cause of death (58% of patients). Allogeneic HCT remains a potentially curative option in selected patients with adult T-ALL, although relapse is a major cause of treatment failure.

HLA-Matched Related (MRD) or Unrelated Donor (URD) Non-Myeloablative Hematopoietic Cell Transplantation (HCT) for Patients (pts) with Refractory and Relapsed Aggressive Non Hodgkin Lymphoma (NHL).

There are few treatment options for pts with relapsed aggressive T and B cell NHL after failure of auto HCT and subsequent high dose allo HCT has resulted in high rates of non-relapse mortality (NRM). We evaluated utility of allo HCT after non-myeloablative conditioning for these pts to reduce NRM risks while exploiting graft versus tumor (GVT) effects. Between 12/1999 and 2/2004, 42 pts, median age 50 (range, 17–66) years, with refractory or relapsed aggressive NHL [diffuse large B cell (DLBCL) (n=32), T-cell anaplastic large cell (ALCL) (n=4), T-cell lymphoblastic (n=3), T- cell immunoblastic (n=2) and Burkitt's (n=1)] were studied. Median time from dx to allo HCT and number of prior regimens were 40 (range, 7–222) months and 4 (range, 1–6), respectively. Twenty-seven pts (62%) had previous auto HCT: 24 had relapsed while 3 had planned auto HCT for cytoreduction before allo HCT. Median time from auto to allo HCT was 15 (range, 2–29) months. Allo conditioning consisted of 2 Gy TBI alone (n = 3 MRD) or with added fludarabine (90 mg/m2) (n = 39; 26 MRD, 13 URD) followed by mycophenolate mofetil and cyclosporin. PBSC (n = 41) or marrow (n = 1) were infused from MRD (n = 29) or URD (n = 13). At HCT, 18 pts were in complete remission (CR) and 24 had measurable disease [10 partial remission (PR) 14 untreated relapse and refractory]. All pts engrafted (see table). The overall incidences of grades II, III and IV acute GVHD were 33%, 15% and 4%, respectively. 2-year probability of chronic GVHD was 57%. Early death from aspergillosis occurred in 2 pts. Of the 18 pts given HCT in CR, 13 (72%) remained in CR after HCT, while 64% of pts (7/11) who were in PR and 23% of pts (3/13) who had relapsed/refractory disease at HCT, achieved CR. The overall response rate was 46%. Of the 24 pts who had relapsed after auto HCT, 2 died early, 11 (46%) achieved CR and 11 progressed after allo HCT. With a median follow up of 19 (range, 6–50) months, 20 of 42 pts (48%) (12 MRD, 8 URD) were alive: 18 in CR (43%) (10 MRD, 8 URD) and 2 with progressive disease. Twenty two pts died a median of 5 (range, 3–26) months after HCT: 14 from relapse and 8 from non-relapse causes (7/8 from infections + GVHD). Day 100, and 1-year NRM* were 10% and 15%, respectively. One year overall* (OS) and progression free survivals* (PFS), and relapse rates* were 63% (MRD: 62%; URD: 85%), 49% (MRD: 45%; URD: 62%) and 36% (MRD: 34%; URD: 38%), respectively. Allo HCT after non-myeloablative conditioning offers a therapeutic option for pts with relapsed aggressive NHL including those in relapse after auto HCT, especially when the disease can be cytoreduced before HCT.All pts (n=42)MRD (n=29)URD (n=13)Disease status at HCT18 CR, 10 PR, 10 Rel, 4 Ref12 CR, 8 PR, 6 Rel, 3 Ref6 CR, 2 PR, 4 Rel, 1 RefOverall response rate11/24 (46%);(10 CR, 1 PR)8/17 (47%);(7 CR, 1 PR)3/7 (43%); (3 CR)CR at HCT, sustained CR13/18 (72%)8/12 (67%)5/6 (83%)PR at HCT, sustained CR7/11 (64%)5/9 (56%)2/2 (100%)Rel or Ref at HCT, sustained CR3/13 (23%)2/8 (25%)1/5 (20%)Living pts status18 CR, 2 PD10 CR, 2 PD8 CRDay 100 NRM*10%14%0%1 year NRM*15%21%0%1 year OS*63%62%63%1 year PFS*49%45%62%1 year Rel rate*36%34%38%Rel : Relapse; Ref : Refractory;*Cumulative probability